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  Carboxamido opioid compoundsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Radical -xh Acid, Or Anhydride, Acid Halide Or Salt Thereof (x Is Chalcogen) Doai, Carboxylic Acid, Percarboxylic Acid, Or Salt Thereof (e.g., Peracetic Acid, Etc.), Nitrogen Other Than As Nitro Or Nitroso Nonionically Bonded, Rc(=o)n Containing (i.e., Carboxamide) (r Is C Or H)The Patent Description & Claims data below is from USPTO Patent Application 20070244194. Brief Patent Description - Full Patent Description - Patent Application Claims
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT [0001] The research and development of the invention described below was not federally sponsored. BACKGROUND OF THE INVENTION [0002] Tramadol hydrochloride, (1RS, 2RS)-2-(dimethyl-amino)-methyl-1-(3-methoxyphenyl)-cyclohexanol HCl (tramadol), is a centrally-acting analgesic that has an unexpected distinction from morphine, the prototype pure opioid analgesic. Although tramadol was introduced into clinical practice in the 1970s without expectation of mechanistic differences from opiates, the data gathered to date in preclinical studies, clinical trials, epidemiological reports, and widespread use in patients indicate that a differentiation is appropriate. [0003] Tramadol is an atypical centrally acting analgesic in that its efficacy appears to be attributable to multiple mechanisms of action. The compound and its enantiomers bind with weak affinity to rodent and human .mu.-opioid receptors and with less affinity for .delta.- or .kappa.-Opioid receptors. Tramadol's O-desmethyl metabolite binds with higher affinity than the parent compound, but still with much lower affinity than morphine. Thus, activation of .mu.-opioid receptors appears to be one of the components of tramadol's mechanism of action, but insufficient on its own to explain tramadol's antinociceptive and analgesic potency and efficacy. [0004] A second, non-opioid component is suggested by several observations that include the incomplete naloxone reversibility in most animal models and in human trials; and, the attenuation of its antinociceptive or analgesic effect by non-opioid antagonists. Hence, the results are consistent with dual contributions, opioid and non-opioid, with the predominant contribution perhaps being dependent upon the species, route of administration, or particular nature of the pain. The source of the dual mechanisms has been hypothesized to arise from the different pharmacologies of the two enantiomers of tramadol, one being more opioid-like than the other. [0005] Analgesics that operate via the .mu.-opioid receptor are typically phenols and phenol ethers. They frequently suffer from the drawback that they are metabolically inactivated by conversion to glucuronides, which are rapidly excreted. The carboxamide group has been found to be an effective bioisosteric surrogate for the phenol group in certain benzomorphans and morphinans, which has led to a series of opioids with a superior biological lifetime (Wentland, M. P. et al. Bioorg. Med. Chem. Lett. 2001, 11(5), 623-6; Wentland, M. P. et al. Bioorg. Med. Chem. Lett. 2001, 11(13), 1717-1721; Bidlack, Jean M. et al. J. Pharmacol. Exp. Ther., 2002, 302(1), 374-380). [0006] The preparation of certain 1-aryl -(2-dialkylaminomethyl)cycloclohexan-1-ols is disclosed in PCT application WO 03/080557 (CA2480038), issued Oct. 10, 2003 (Sundermann, B. et al, Grunenthal GMBH Assignee.). A genus of tramadol analogs is disclosed in PCT application WO 03/048113, issued Jun. 12, 2003 (Senanayake, C. H. et al., Seprecor Assignee). [0007] Thus there is a need to address the metabolic inactivation of tramadol that occurs through the conversion of its hydroxy metabolite to the corresponding glucuronide. The present invention replaces the methoxy substituent of tramadol with a carboxamido group. SUMMARY OF THE INVENTION [0008] The present invention provides carboxamido opioid compounds of Formula (I): wherein: [0009] R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen, lower alkyl, and alkyldiyl wherein R.sup.1 and R.sup.2 are taken together with the atoms to which they are attached to form a monocyclic ring; [0010] R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, lower alkyl, C.sub.3-7cycloalkyl, and alkyldiyl wherein R.sup.3 and R.sup.4 are taken together with the atoms to which they are attached to form a monocyclic ring; [0011] Y is hydrogen, lower alkyl, lower alkoxy, halogen, or trifluoromethyl; and pharmaceutically acceptable enantiomers, diastereomers, tautomers, solvates and salts thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0012] FIG. 1 shows the antihyperalgesic effect of Compounds 3 and 4 in a rat CFA radiant heat model of inflammatory pain. [0013] FIG. 2 shows the analgesic effect of Compound 3 in a spinal nerve ligation (SNL) model of neuropathic pain. [0014] FIG. 3 shows the results of a study of the development of tolerance to the antiallodynic effect of Compound 3. [0015] FIG. 4 shows the results of a study of the development of tolerance to the antiallodynic effect of morphine. DETAILED DESCRIPTION OF THE INVENTION [0016] Embodiments of the present invention include those compounds of Formula (I) wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen and C.sub.1-4alkyl. [0017] Embodiments of the present invention include those compounds of Formula (I) wherein R.sup.1 and R.sup.2 are independently selected from the group consisting of hydrogen and methyl. [0018] Embodiments of the present invention include those compounds of Formula (I) wherein R.sup.1 and R.sup.2 are each methyl. [0019] Embodiments of the present invention include those compounds of Formula (I) wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, C.sub.1-4alkyl, C.sub.3-7cycloalkyl, and C.sub.1-4alkyldiyl wherein R.sup.3 and R.sup.4 are taken together with the atoms to which they are attached to form a monocyclic ring. [0020] Embodiments of the present invention include those compounds of Formula (I) wherein R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen, methyl, and cyclopropyl. [0021] Embodiments of the present invention include those compounds of Formula (I) wherein R.sup.3 and R.sup.4 are each hydrogen. [0022] Embodiments of the present invention include those compounds of Formula (I) wherein Y is hydrogen, C.sub.1-4alkyl, C.sub.1-4alkoxy, or halogen. Continue reading... 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